Acute myeloid leukemia with an MN1-ETV6 fusion in a young child with Down syndrome

Abstract

Myeloid leukemia of Down syndrome (ML-DS) in young children is associated with distinct clinical and biological features and is typically initiated with oncogenic mutations in the X-linked megakaryocytic transcription factor GATA1. Here we present a 3-yr-old child with DS diagnosed with acute myeloid leukemia (AML), which lacks typical immunophenotypic and molecular characteristics of ML-DS, including GATA1 mutations. The leukemic blasts were found to have an MN1-ETV6 gene fusion, a high-risk oncofusion not previously described in DS patients. This report highlights the importance of immunophenotypic, cytogenetic, and molecular characterization of ML-DS for identification of rare cases with unique features that may benefit from treatment protocols that are more intensive than those developed for patients with typical GATA1 mutant ML-DS.

Trial registration: ClinicalTrials.gov NCT01775072.

Keywords: acute myeloid leukemia; leukemia.

Figure 1.

Cytogenetic and molecular evaluation of the patient's leukemia cells at diagnosis. (A) Chromosome analysis identifies a clone with constitutional trisomy 21 and somatic gain of Chromosome 8 and t(12;21;22) (arrows). (B) Fluorescence in situ hybridization (FISH) analysis using ETV6 break-apart probes shows a split signal pattern of the 5′ and 3′ probes, confirming ETV6 translocation. (C) MN1-ETV6 fusion schematic as identified by RNA sequencing. (PNT) Pointed domain, (ETS) ETS DNA binding domain.

Figure 2.

Immunophenotypic comparison between typical GATA1 mutant myeloid leukemia of Down syndrome (ML-DS) and this patient with MN1-ETV6 AML. The gating used to identify the abnormal progenitor cells combining forward and side scatter in combination with CD45 is demonstrated in A and B. (A) The recurrent phenotype of GATA1 mutant ML-DS (bright green) is HLA-DR-negative, CD11b-positive, CD7-bright, CD117-positive, and CD36 without expression of CD64. Expression of other antigens is variable including CD34, CD38, CD13, CD33, and the platelet antigens CD41, CD42b, and CD61. (B) The phenotype of the MN1-ETV6 AML (yellow) was characterized by heterogeneous expression of HLA-DR, dim CD7, and heterogeneous CD117 without expression of CD36. The abnormal cells in this case expressed CD34.